PRINCE: Phase I trial of <sup>177</sup>Lu-PSMA-617 in combination with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shahneen Sandhu, Anthony M. Joshua, Louise Emmett, Lavinia Anne Spain, Lisa Horvath, Megan Crumbaker, Angelyn Anton, Roslyn Wallace, Anupama Pasam, Mathias Bressel, Erin Cassidy, Patricia Banks, Nattakorn Dhiantravan, Timothy J. Akhurst, Aravind Ravi Kumar, Ramin Alipour, Mark Scalzo, Scott Williams, Rodney Hicks, Michael S Hofman
Journal: Journal of Clinical Oncology (2022)

5017 Background: The VISION and TheraP trials have established the safety and efficacy of 177 Lu-PSMA-617 in mCRPC with a 50% PSA response rate (PSA50-RR) of 46% and 66% and median progression free survival (PFS) of 8.7 and 5.1 months, respectively. More effective treatments are required as disease progression remains universal. Immunotherapy has limited single-agent efficacy in mCRPC. We hypothesise that by potentially inducing immunogenic cell death, 177 Lu-PSMA-617 may act synergistically with pembrolizumab, an anti-programmed death 1 inhibitor, to enhance the depth and durability of response. PRINCE is a Phase I trial evaluating the safety and efficacy of this combination. Methods: mCRPC patients with high PSMA expression (SUVmax ≥ 20 in an index lesion, SUVmax &gt; 10 for all lesions ≥ 10mm), and no FDG+ve/PSMA-ve lesions on paired baseline PET/CT screening, received up to 6 cycles of 177 Lu-PSMA-617 (starting at 8.5 GBq, reducing by 0.5 GBq with each cycle) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. Response evaluation was undertaken as per PCWG3 and RECIST criteria. Co-primary endpoints were safety and PSA50-RR. Secondary endpoints included PSA-PFS, radiographic PFS (rPFS), overall survival (OS), and patient reported outcomes (PROs). This analysis was undertaken after the last patient had 12 months follow-up. Results: 37 patients (median age 72 years; prior docetaxel 73%; prior androgen receptor targeted agent 100%) received a median of 5 cycles (range: 2 to 6) of 177 Lu-PSMA-617 and 12 doses (range: 6 to 19) of pembrolizumab. The median follow up was 16 months. PSA50-RR was 76% (28/37 [95% CI 59-88]) and 7/10 (70%) patients with RECIST-measurable disease had a partial response. Median rPFS, PSA-PFS and OS was 11.2 months (95% CI: 5.1-14.1), 8.2 months (95% CI: 5.1-11.2) and 17.8 months (95% CI:13.4-not estimable). 12-month rPFS and OS was 38% (95% CI: 22-54) and 83% (95% CI: 67-92), respectively. Common (≥10%) treatment-related adverse events (TRAE) were mainly Grade (G) 1-2, including xerostomia (78%), fatigue (43%), pruritus (27%), nausea (27%), rash (24%), diarrhoea (14%), anorexia (16%), thrombocytopenia (16%), elevated ALT (11%), arthralgia (11%) and a flare in bone pain (11%). Haematologic TRAEs included G2-3 anaemia (8%), G1-2 thrombocytopenia (16%), and G1 neutropenia (3%). G3 immune-related AEs occurred in 10 (27%) patients with no dominant manifestation. 5 (14%) patients discontinued pembrolizumab due to toxicity. PROs including BPI-SF and FACT-P were stable throughout the study. Conclusions: The combination of 177 Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were generally consistent with those of single-agent 177 Lu-PSMA-617 and pembrolizumab and were not clearly augmented by combination use. No new safety concerns were observed. Clinical trial information: NCT03658447.